The compounds of the present invention are inhibitors of interleukin-1.beta. converting enzyme (ICE) and are useful in treating diseases in which interleukin-1 plays a role.
ICE acts on pro-interleukin-1.beta. (pro-IL-1.beta.) to produce interleukin-1.beta. (IL-1.beta.), which is an inflammatory cytokine. In addition, ICE (Caspase-1) regulates at least four cytokines. ICE activates IL-.beta. and IL-18, and indirectly regulates the production of IL1.varies. and IFN.gamma.. Several diseases are associated with excessive interleukin-1 activity. Examples of diseases in which interleukin-1 is involved include, but are not limited to, inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease, and neuroinflammatory disorders such as stroke. Other diseases include septic shock, reperfusion injury, Alzheimer's disease, and shigellosis.
Agents that modulate IL-1.beta. activity have been shown to have beneficial in vivo effects. For example, compounds that are interleukin-1 receptor antagonists have been shown to inhibit ischemic and excitotoxic damage in rat brains. See, for example, Relton J. K., et al., Brain Research Bulletin, 1992;29:243-246. Additionally, ICE inhibitors were shown to reduce inflammation and pyrexia in rats. See Elford P. R., et al., British Journal of Pharmacology, 1995; 115:601-606.
The compounds of the present invention are also inhibitors of other cysteine proteases in the ICE family. Many of these proteases have only recently been described in the literature. While the nomenclature is still unresolved, the following proteases are representative members of this class of enzymes; Ich-2 (also called Tx or ICErel-II), ICErel-III, Ich-I (also called Nedd-2), CPP-32 (also called apopain and yama), Mch-2, Mch-3 (also called ICE-lap3, CMH-1), and Ced-3. See Henkart P. A., Immunity, 1996;4:195-201. It is recognized that members of this enzyme family play key biological roles in both inflammation and apoptosis (programmed cell death). In particular, Caspase-4 can activate IL-1.beta. and IL-18. It has been shown that a murine homolog of Caspase-4 can activate ICE. Thus, inhibition of Caspase-4 will act to inhibit ICE. See Thornberry N. A., et al., Perspectives in Drug Discovery and Design, 1994;2:389-399.
In addition to its effects on IL-1.beta. production, ICE has been shown to play a role in the production of the inflammatory mediator interferon-.gamma. (Ghayur, et al., Nature, 1997;386(6625):619-623). ICE processes the inactive proform of interferon-.gamma. inducing factor (IGIF; Interleukin-18) to active IGIF, a protein which induces production of interferon-.gamma. by T-cells and natural killer cells. lnterferon-.gamma. has been implicated in the pathogenesis of diseases such as inflammatory disorders and septic shock. Therefore, ICE inhibitors would be expected to have beneficial effects in such disease states by effects on interferon-.gamma..
Recently, the nomenclature of these cysteine proteases in the ICE family (also known as Caspases with ICE being known as Caspase-1) has been further defined. The following proteases are representative members of this class of enzymes using the nomenclature described in Alnemri, et al., Cell, 1996;87:171: Caspase-2 (also known as Ich-1); Caspase-3 (also known as CPP32, Yama, and apopain); Caspase-4 (also known as TX, Ich-2, and ICE rel-II); Caspase-5 (also known as ICE rel-III); Caspase-6 (also known as Mch2); Caspase-7 (also known as Mch3); Caspase-8 (also known as FLICE and Mch5); Caspase-9 (also known as ICE-LAP6 and Mch6); Caspase-10 (also known as Mch4).